Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, Unresectable Breast Cancer

- This is a phase 1b, open-label, non-randomized, fixed dose study in patients with HER2
negative metastatic, or locally advanced, unresectable breast cancer.

- Cirmtuzumab and paclitaxel will be administered until disease progression or
unacceptable toxicity. Cirmtuzumab or paclitaxel may be continued alone if the other
drug is discontinued due to toxicity, as long as the subject is tolerating the drug and
does not exhibit disease progression.

- Blood and tissue samples will be collected at pre-specified times to enable
pharmacokinetic and correlative studies.

- Adverse events (AE) will be monitored throughout the trial. Reporting of AEs will be in
accordance with CTCAE version 4.03.

- Assessment of tumor response will be performed by physical examination and/or by
radiographic imaging and according to the Response Evaluation Criteria in Solid Tumors
(RECIST) v.1.1.

- Patients will be assessed at 28 days following the last dose of cirmtuzumab to assess
tumor response and at 56 days following the last dose of cirmtuzumab to assess any
adverse events and to document any concomitant cancer therapy.

INCLUSION CRITERIA:

- Biopsy-confirmed, metastatic or locally advanced surgically unresectable, HER2
negative breast cancer. HER2 status should reflect the most recent biopsy results.
Note: HER2 negative breast cancer is defined according to the American Society of
Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines 2013 for
HER2 testing performed in a CLIA-certified laboratory.

- ER/PR negative (<10% of cells staining for ER or PR) breast cancer or have ER/PR
positive (≥10% of cells staining for ER or PR) breast cancer that has exhausted
standard endocrine therapy and/or in the opinion of the treating oncologist, warrants
cytotoxic chemotherapy.

- Measurable disease as defined by RECIST v1.1. Measurable lesions will be confirmed by
radiographic imaging (CT or MRI). Patients with bone only disease will be eligible if
disease is considered measurable and a soft tissue component is present and can be
biopsied..

- There is no limit to prior lines of therapy, but patients must not have received prior
taxane chemotherapy in the metastatic setting.

- ECOG Performance Status ≤ 2.

- Adequate organ function as defined below:

- Absolute Neutrophil Count ≥ 1.0 x 10^9/L

- Platelet count ≥ 100,000 /μL

- Hemoglobin ≥ 8.0 g/dL

- Total bilirubin ≤ 1.5 x upper limit of normal

- AST and ALT ≤ 3 x upper limit of normal

- Serum creatinine ≤ 2 x upper limit of normal OR Creatinine clearance > 40
ml/min/1.73 m^2

- Women of child-bearing potential and male subjects who are sexually active with a
woman of childbearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation, and for at least 6 months following last infusion of cirmtuzumab.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.

- Existing neuropathy must be no greater than Grade 1.

- No concurrent antibody therapy can be planned with the exception of denosumab for use
in bone metastasis.

- CNS metastases are allowed as long as the metastases are asymptomatic, have been
treated with radiation, and have been stable for > 6 weeks off steroids.

EXCLUSION CRITERIA:

- Patient is currently receiving chemotherapy or has received another chemotherapy
within 5 half-lives, radiotherapy or immunotherapy within 2 weeks prior to study
treatment initiation.

- Patient has known, untreated and/or symptomatic central nervous system (CNS)
metastases and/or carcinomatous meningitis.

- Patient had disease that was refractory to paclitaxel in the neoadjuvant setting
and/or developed metastatic breast cancer within 6 months of neoadjuvant or adjuvant
taxane chemotherapy.

- Patient has had major surgery within 3 weeks prior to enrollment.

- Patient has severe and/or uncontrolled medical disease(s) (i.e., myocardial infarction
within 6 months of study, CKD stage IV or above, severe chronic pulmonary disease or
active infection).

- The patient has known acute or chronic hepatitis B or C.

- The patient has a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to paclitaxel.

- The patient has a history of another malignancy within 2 years prior to study entry,
except curatively treated non-melanotic skin cancer, cervical carcinoma in situ or
stage I colon cancer.

- Patient has a history of non-compliance or other medical illness that would preclude
compliance with study procedures.

- Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.

- Patient has severe cardiac insufficiency (NYHA III or IV) with uncontrolled and/or
unstable cardiac or coronary artery disease

- Patient is pregnant or nursing. There is a potential for congenital abnormalities and
for this regimen to harm nursing infants.